Sulfonamido substituted benzopyran derivatives

ABSTRACT

ts thereof wherein Y is a single bond, -CH2-, -C(O)-, -O-, -S- or -N(R14)-; and R1 to R7 are as defined herein. These compounds have potassium channel activating activity and are useful, therefore for example, as cardiovascular agents.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention novel compounds havingpotassium channel activating activity which are useful, for example, ascardiovascular agents, are disclosed. These compounds have the generalformula ##STR2## wherein ##STR3## R¹ is R² is hydrogen, hydroxy, or--OC(O)R¹⁴ ;

R³ and R⁴ are each independently hydrogen, alkyl or arylalkyl; or R³ andR⁴ taken together with the carbon atom to which they are attached form a3- to 7-membered carbocyclic ring;

R⁵ is hydrogen, alkyl, halogen, heterocyclo, nitrile, haloalkyl or aryl;

R⁶ and R⁷ are independently hydrogen, alkyl, cycloalkyl, aryl,arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkyl substituted with acarboxylic ester or carboxylic acid, alkoxyalkyl, thioalkyl,(cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyl;

or R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a 5- to 7-membered mono or bicyclic ring including fusedrings such as 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 4-thiamorpholine dioxide, 1-piperazinyl,4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl,4-diarylalkyl-1-piperazinyl; or 1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl or 1-azepinyl substituted with one or more alkyl, alkoxy,alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, --COOR¹⁴ or--CO-substituted amino;

or R⁵ and R⁶ taken together with the atoms to which they are attachedform a 5- to 7-membered ring optionally substituted with aryl;

R⁸ is aryl, arylalkyl, heterocyclo or (heterocyclo)alkyl;

R⁹ is hydrogen or alkyl;

or R⁸ and R⁹ taken together with the nitrogen atom to which they areattached form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl or4-arylalkyl-1-piperazinyl, wherein each of the so-formed groups can besubstituted with alkyl, alkoxy, alkylthio, halogen or trifluoromethyl;

R¹⁰ and R¹¹ are independently hydrogen, alkyl, alkenyl, aryl, arylalkyl,cycloalkyl or cycloalkylalkyl; or R¹¹ can be an aryl group fused to 2carbon atoms of the cyanoguanidine ring portion;

R¹² is aryl or heterocyclo;

R¹³ is --COOR¹⁴, --CO-amino, --CO-substituted amino, amino, substitutedamino, --NR¹⁴ CO-amino, --NR¹⁴ CO-substituted amino, --NR¹⁴ COR¹⁵,--NR¹⁴ SO₂ R¹⁵, --NR¹⁴ (C═NCN)-amino, --NR¹⁴ (C═NCN)-substituted amino,##STR4## --SR¹⁴, --SOR¹⁴, --SO₂ R¹⁴, --OR¹⁴, cyano, heterocyclo,pyridine-N-oxide, --CH(OR¹⁴)₂, ##STR5## R¹⁴ and R¹⁵ are independentlyhydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkyl or(cycloalkyl)alkyl;

X is alkyl; or X--R¹³ together can be hydrogen, aryl or heterocyclo whenR¹² is heterocyclo;

Y is a single bond, --CH₂ --, --C(O)--, --O--, --S-- or --N(R¹⁴)--;

Z is NCN, S or O; and

n is an integer of 1 to 3.

The compounds of this invention possess antiischemic activity and areuseful, for example as cardiovascular agents.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the sulfonamido compounds of formula I above,to compositions and the methods of using such compounds. The compoundsof formula I are useful, for example, as cardiovascular agents.

Listed below are definitions of various terms used to describe thecompounds of the instant invention. These definitions apply to the termsas they are used throughout the specification (unless they are otherwiselimited in specific instances either individually or as part of a largergroup).

The term "alkyl" refers to both straight and branched chain groupshaving 1 to 8 carbon atoms preferably 1 to 5 carbons, such as methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, the various branchedchain isomers thereof, such as isopropyl, t-butyl, isobutyl, isohexyl,4,4-dimethylpentyl, 2,2,4-trimethylpentyl and the like as well as suchgroups optionally substituted with one or more substituents selectedfrom halogen, alkoxy, aryl, alkylaryl, haloaryl, cycloalkyl,(cycloalkyl)alkyl, hydroxy, alkylamino, alkyl-substituted amino,alkanoylamino, arylcarbonylamino, nitro, cyano, thiol, alkylthio or--COOR¹⁴.

The term "alkoxy" refers to any of the above alkyl groups linked to anoxygen atom.

The term "alkylthio" refers to any of the above alkyl groups linked to asulfur atom.

The term "alkenyl" refers to any of the above alkyl groups having atleast 2 carbon atoms further containing at least one carbon to carbondouble bond.

The term "alkynyl" refers to any of the above alkyl groups having atleast 2 carbon atoms further containing at least one carbon to carbontriple bond.

The term "cycloalkyl" refers to saturated cyclic hydrocarbon groupscontaining 3 to 7 ring carbons with cyclopropyl, cyclopentyl andcyclohexyl being preferred.

The term "halogen" or "halo" refers to chlorine, bromine, iodine andfluorine.

The term "aryl" refers to phenyl, 1-naphthyl or 2-naphthyl; phenyl,1-naphthyl or 2-naphthyl, mono-substituted with (C₁ -C₄)-alkyl, (C₁-C₄)-alkylthio, (C₁ -C₄)-alkoxy, halo, nitro, cyano, hydroxy, amino,(alkyl)amino, alkyl-substituted amino, --NH--(C₁ -C₄)-alkyl, --N((C₁-C₄)-alkyl)₂, heterocyclo, --CF₃, --OCHF₂, ##STR6## (where Z¹ ishydrogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkoxy, halo,hydroxy or --CF₃), --O--CH₂ -cycloalkyl, or --S--CH₂ -cycloalkyl; orphenyl, 1-naphthyl or 2-naphthyl, di-substituted with methyl, methoxy,methylthio, halo, --CF₃, nitro, amino, --OCHF₂, carboxylic acid orcarboxylic ester. The term "aryl" also includes those groups listedabove fused to a five- or six-membered ring which optionally contains anO, S or N atom (the nitrogen atom being substituted by hydrogen, alkyl,alkoxy, hydroxy, amino, substituted amino, --NHCOR¹⁴, --CN or --NO₂).Preferred aryl groups include unsubstituted phenyl and monosubstitutedphenyl wherein the substituents are (C₁ -C₄)-alkyl, methoxy, halo,nitro, cyano or --CF₃.

The term "heterocyclo" or "hetero" refers to fully saturated orunsaturated rings of 5 or 7 atoms containing one or two oxygen and/orsulfur atoms and/or one to four nitrogen atoms provided that the totalnumber of hetero atoms in the ring is four or less. The hetero ring isattached by way of an available atom. Preferred monocyclic hetero groupsinclude 2- and 3-thienyl, 2- and 3-furyl, 2-, 3- and 4-pyridyl,imidazolyl, thiazole, oxazole, pyrazole, isoxazole and isothiazole. Theterm "hetero" also includes bicyclic rings wherein the five- orsix-membered ring containing oxygen and/or sulfur and/or nitrogen atomsas defined above is fused to a benzene ring and the bicyclic ring isattached by way of an available carbon atom. Preferred bicyclic heterogroups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-,6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or7-benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl and 4-, 5-, 6- or7-benzofuranzanyl.

The term "heterocyclo" or "hetero" also includes such monocyclic andbicyclic rings wherein an available carbon atom is substituted with a(C₁ -C₄)-alkyl, aryl, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkoxy, halo, nitro,keto, cyano, hydroxy, azo, thiazo, amino, --NH--(C₁ -C₄ )-alkyl, --N((C₁-C₄)-alkyl)₂, --CF₃, (aminoester)alkyl, carboxylic acid, carboxylicester, --OCHF₂ or (C₁ -C₄)-alkoxy further substituted with a carboxylicacid or such monocyclic and bicyclic rings wherein two or threeavailable carbons have substituents selected from methyl, methoxy,methylthio, halo, --CF₃, nitro, hydroxy, amino and --OCHF₂.

The term "substituted amino" refers to a group of the formula --NZ² Z³wherein Z² is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl,(cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or (heterocyclo)alkyland Z³ is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, thioalkyl, (cycloalkyl)alkyl or hydroxyalkylfurther substituted with a carboxylic ester or carboxylic acid, with theproviso that when Z² is hydrogen, then Z³ is other than hydrogen; or Z²and Z³ taken together with the nitrogen atom to which they are attachedare 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl,4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4diarylalkyl-1-piperazinyl; or 1-pyrrolidinyl,1-piperidinyl, 1-azepinyl substituted with alkyl, alkoxy, alkylthio,halo, trifluoromethyl or hydroxy.

The compounds of formula I can be present as salts, in particularpharmaceutically acceptable salts. If the compounds of formula I have,for example, at least one basic center, they can form acid additionsalts. These are formed, for example, with strong inorganic acids, suchas mineral acids, for example sulfuric acid, phosphoric acid or ahydrohalic acid, with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted, for example, by halogen, for example acetic acid, such assaturated or unsaturated dicarboxylic acids, for example oxalic,malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, suchas hydroxycarboxylic acids, for example ascorbic, glycolic, lactic,malic, tartaric or citric acid, such as amino acids, (for exampleaspartic or glutamic acid or lysine or arginine), or benzoic acid, orwith organic sulfonic acids, such as (C₁ -C₄)-alkyl- or aryl-sulfonicacids which are unsubstituted or substituted, for example by halogen,for example methane- or p-toluene-sulfonic acid. Corresponding acidaddition salts can also be formed having, if desired, an additionallypresent basic center. The compounds of formula I having at least oneacid group (for example COOH) can also form salts with bases. Suitablesalts with bases are, for example, metal salts, such as alkali metal oralkaline earth metal salts, for example sodium, potassium or magnesiumsalts, or salts with ammonia or an organic amine, such as morpholine,thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-loweralkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-,triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- ortrihydroxy lower alkylamine, for example mono-, di- or triethanolamine.Corresponding internal salts may furthermore be formed. Salts which areunsuitable for pharmaceutical uses but which can be employed, forexample, for the isolation or purification of free compounds of formulaI or their pharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of formula I include monohydrochloride,hydrogensulfate, methanesulfonate, phosphate or nitrate.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents.Consequently, compounds of formula I can exist in diastereomeric formsor in mixtures thereof. The below described processes can utilizeracemates, enantiomers or diastereomers as starting materials. Whendiastereomeric products are prepared, they can be separated byconventional methods for example, chromatographic or fractionalcrystallization. Preferred compounds are those with the 3R or 4Sstereochemistry.

It should be understood that the present invention includes prodrugforms of the compounds of formula I such as alkylesters of acids.

The compounds of the instant invention may, for example, be in the freeor hydrate form, and may be obtained by methods exemplified by thefollowing descriptions.

Preparation of Compounds of Formula IA Compounds of formula ##STR7##i.e. compounds of formula I where R¹ is ##STR8## and Z is NCN areprepared by treatment of a thiourea of the formula ##STR9## with anamine of the formula ##STR10## in the presence of a coupling agent, suchas a carbodiimide, in a solvent, such as dimethylformamide,tetrahydrofuran, acetonitrile or dichloromethane. Preferably, thecarbodiimide is of the formula ##STR11## wherein X' halogen, R^(a),R^(b) and R^(c) are independently alkyl, cycloalkyl, phenyl,phenylalkyl, cycloalkylalkyl or R^(a) and R^(b) together with thenitrogen atom to which they are attached form 1-pyrrolidinyl,1-piperidinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-alkyl-1-piperazinylor 4-phenylalkyl-1-piperazinyl. Most preferably the carbodiimide offormula IV is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride.

The compounds of formula IA where Z is NCN can also be prepared byreacting an amine of formula III with diphenylcyanocarbonimidate toproduce a compound of the formula ##STR12## Reaction of a compound offormula V with an amine of the formula

    R.sup.8 R.sup.9 NH                                         VI

in a polar solvent such as isopropanol produces the compounds of formulaIA (where Z is NCN).

Compounds of the formula IA where Z is oxygen or sulfur can be preparedby reacting an amine of the formula III with a compound of formula##STR13## where L* is a leaving or activating group in an organicsolvent such as dimethylformamide, tetrahydrofuran, acetonitrile ordichloromethane. Suitable leaving or activating groups include chlorine,4-nitrophenyloxy and phenoxy.

Compounds of formula 1A where Z is oxygen or sulfur and R⁹ is hydrogencan be made by reacting amine III with a compound of formula

    R.sup.8 --N═C═Z                                    VIII

where Z is oxygen or sulfur.

The thiourea of formula II, wherein R⁹ is hydrogen can be prepared byheating an isothiocyanate of the formula

    R.sup.8 N═C═S                                      IX

with either monosodium cyanamide or with cyanamide in the presence of anorganic base, such as triethylamine.

The other thioureas of formula II can be prepared by standard methodsdescribed in the literature, such as by C. R. Rasmussen et al.,Synthesis, p. 456 (1988), and V. V. Mozolis et al., Russian ChemicalReviews, 42, p. 587 (1973).

The amino alcohol of formula III where R² is hydroxyl can be preparedfrom 4-hydroxybromobenzene by methods described in the literature suchas J. M. Evans et al., J. Med. Chem., 26, 1582 (1983) and J. Med. Chem.,29, 2194 (1986); R. W. Lang et al., Helvetica Chimica Acta, 71, 596(1988); EP 0205292 (1986); WO 87/07607; and K. S. Atwal et al., J. Med.Chem., 36, 3971 (1993) to form the bromides of formula ##STR14## where Yis oxygen. Successive treatments of the bromides of formula X withn-butyllithium, liquid sulfur dioxide and sulfuryl chloride producessulfonyl chlorides of formula ##STR15## Treatment of thesulfonylchlorides of formula XI with an amine of formula ##STR16## in anorganic solvent in the presence of a base such as triethylamine ordiisopropylethylamine produces the olefins of formula ##STR17##Epoxidation of the olefins of formula XIII with commercial bleach,m-peroxylchlorobenzoic acid or dimethyldioxirane in the presence of achiral manganese catalyst of formula ##STR18## as described by N. H.Lee, et al., Tetrahedron Letters, 32, p. 5055-5058 (1991), produces theepoxides of formula ##STR19## Either enantiomer of epoxide XV can beprepared depending on the chirality of catalyst XIV or racemic mixturesof formula XIV can be obtained by treatment with m-peroxylchlorobenzoicacid in an organic solvent such as dichloromethane. Subsequent treatmentof the epoxide of formula XV with an amine of formula

    R.sup.10 NH.sub.2                                          XVI

or ammonium hydroxide in an organic solvent such as tetrahydrofuran orethanol produces the amino alcohol of formula III, where R₂ is hydroxyl.

Compounds of formula III where R² is hydrogen, can be prepared fromcompounds of formula XIII by a sequence of steps which involve (a)catalytic hydrogenation (b) radical bromination and (c) displacement ofbromide with an amine of formula XVI.

Compounds of formula X wherein Y is --O-- can be prepared according toTetrahedron Letters, 35, p. 6405-6408 (1994) and references citedtherein.

Compounds of formula X wherein Y is a single bond or --N(R¹⁴)-- can beprepared according to D. R. Buckle, et al., J. Med. Chem., 34, p. 919(1991).

Compounds of formula X wherein Y is --CH₂ -- can be prepared by methodsdescribed in V. A. Ashwood, et al., J. Med. Chem., 34, p. 3261 (1991).

Compounds of formula X wherein Y is --C(O)-- may be prepared by methodsdescribed by C. Almansa et al., J. Med. Chem., Vol. 36, p. 2121-2133(1993).

Compounds of formula X wherein Y is --S-- can be prepared according tothe methods described by D. Smith et al., EP-0322251.

The compounds formula IA where Z is sulfur can be prepared by convertinga compound of formula III by standard methods (i.e., the Rasmussen andMozolis references cited above) to a thiourea of the formula ##STR20##Subsequent heating with monosodium cyanamide in the presence of acarbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide in an organic solvent produces the compounds offormula IA (where Z is S).

Most of the compounds of formula IV, VI, IX, XII and XVI arecommercially available or can be prepared by standard methods describedin text books of organic chemistry such as Introduction to OrganicChemistry by A. Streitwieser and C. H. Heathcock, Macmillan PublishingCo., Inc., N.Y. (1976).

Preparation of Compounds of Formula IB The compounds of formula##STR21## i.e. compounds of the formula I wherein R¹ is ##STR22## and Zis NCN can be prepared by treating a diamine of the formula ##STR23##with dimethyl-N-cyanodithioiminocarbonate to form compounds of theformula ##STR24## Subsequent treatment with mercuric acetate in analcoholic solvent such as methanol produces the compounds of formula IB(where Z is NCN).

Compounds of formula IB wherein Z is oxygen or sulfur can be preparedfrom compounds of formula XVIII by treatment with phosgene(thiophosgene) or p-nitrophenylchloroformate in the presence of anorganic base such as pyridine or triethylamine.

The compounds of formula IB where Z is NCN can also be prepared bytreating a diamine of formula XVIII with diphenylcyano-carbonimidate inan alcoholic solvent, such as 2-propanol.

The compounds of formula XVIII wherein R² is trans hydroxyl are obtainedby treatment of an epoxide of formula XV with a diamine of the formula##STR25## in an alcoholic solvent, such as ethanol.

Compounds of formula XVIII can also be prepared from the amine III andan alkylating agent of the formula ##STR26## wherein P is a protectinggroup such as a phthalamido group and X" is a leaving group, such as Cl,Br or I, in the presence of a base catalyst, such as potassium carbonatefollowed by deprotection.

The compounds of formula IB wherein R² is --OCOR¹⁴ can be prepared byacylation of the alcohols of formula IB, (where R² is hydroxyl), with anacid chloride of the formula ##STR27## in the presence of a basecatalyst, such as pyridine or triethylamine.

Most of the compounds of formula VII, VIII, XX, XXI and XXII arecommercially available, or they can be readily prepared by methodsdescribed in standard text books of organic chemistry, for example,Introduction to Organic Chemistry by A. Streitwieser and C. H.Heathcock, Macmillan Publishing Co., Inc. N.Y. (1976); and AdvancedOrganic Chemistry by F. C. Carey and R. J. Sundberg, Plenum PublishingCo., N.Y. (1977).

Preparation of Compounds of Formula IC Compounds of formula ##STR28##where R² is trans-hydroxy and X is --CH₂ --, can be prepared by firstreacting an epoxide of formula XV with an amine of formula

    R.sup.12 --NH.sub.2                                        XXIII

under heat or preferably in the presence of a Lewis acid such asmagnesium perchlorate or trimethylaluminum to provide an intermediate offormula ##STR29## The intermediate of formula XXIV is then derivatizedby reductive amination using an aldehyde of formula ##STR30## in thepresence of a reducing agent such as sodium cyanoborohydride or sodiumtriacetoxyborohydride. Alternatively, reductive amination can beeffected with hydrogen gas in the presence of a catalyst such aspalladium on carbon.

Compounds of formula IC can also be prepared by reacting an epoxide offormula XV with an amine of formula

    R.sup.12 --NH--X--R.sup.13                                 XXVI

in an organic solvent such as acetonitrile in the presence of a Lewisacid such as magnesium perchlorate or cobalt chloride.

Compounds of formula IC wherein R² is hydroxyl, can also be prepared bytreatment of an epoxide of formula XV with an anion or dianion of thecompound of formula XXVI. The anion or dianion of compound XXVI can beprepared by treatment of the amine of formula XXVI with a strong base(n-butyl lithium, potassium hexamethyldisilazide etc.) in an organicsolvent such as tetrahydrofuran.

Compounds of formula IC wherein R¹³ is CO-amino or CO-substituted amino,can be prepared by reacting compounds of formula IC wherein R¹³ isCOOR¹⁴ with ammonia or an appropriate amine.

Compounds of formula IC where R¹³ is NR¹⁴ CO-amino, NR¹⁴ CO-substitutedamino, NR¹⁴ COR¹⁵, NR¹⁴ SO₂ R¹⁵, NR¹⁴ (C═NCN)-amino or NR¹⁴(C═NCN)-substituted amino can be prepared from compounds of formula ICwhere R¹³ is amino or substituted amino by methods described in theliterature such as those used for acylation, urea formation,sulfonylation and cyanoguanidine formation of organic chemistry, forexample, Introduction to Organic Chemistry by A. Streitwieser and C. H.Heathcock, Macmillan Publishing Co., Inc. N.Y. (1976), and AdvancedOrganic Chemistry by F. C. Carey and R. J. Sundberg, Plenum PublishingCo., N.Y. (1977).

Compounds of formula IC where R¹² is heterocyclo (e.g., benzoxazole) andR² is trans-hydroxy can also be prepared by first reacting an epoxide offormula XV with an amine of formula

    H.sub.2 N--X--R.sup.13                                     XXVII

under heat or in the presence of a Lewis acid such as magnesiumperchlorate or trimethylaluminum to provide an intermediate of formula##STR31## The intermediate of formula XXVIII is then reacted with aheterocycle containing a leaving group (e.g., 2-chloro-benzoxazole) inthe presence of a base such as sodium hydride in an organic solvent suchas tetrahydrofuran or dimethylformamide to form compounds of formula ICwhere R¹² is heterocyclo and R² is trans-hydroxy.

Other compounds of formula IC wherein R¹² is heterocyclo (e.g., oxazole,pyrazole, isoxazole etc.) can be prepared from intermediates of formulaXXVIII by standard methods.

Compounds of formula IC wherein R¹² is heterocyclo (e.g., thiazole) canalso be prepared by alkylation of a compound of formula XXIV with analkylating agent of formula

    L'--X--R.sup.13                                            XXIV

where L' is a leaving group such as a halogen, mesylate or tosylate.

Compounds of formula IC wherein R² is hydrogen can be prepared fromcompounds of formula ##STR32## by reaction with an amine of formula XXVIin the presence of a base such as sodium hydride or potassium carbonate.

Alternatively, compounds of formula IC where R² is hydrogen can beprepared by first reacting a compound of formula XXX with an amine offormula III in the presence of a base (e.g., sodium hydride) to providea compound of formula ##STR33## The compound of formula XXXI is thenconverted to compounds of formula IC where R² is hydrogen by methodsdescribed for the conversion of compounds of formula XXIV to compoundsof formula IC. Compounds of formula XXXI where R² is hydrogen can alsobe prepared from compounds of formula XXIV by (a) dehydration of thealcohol with sodium hydride in aprotic solvents such as tetrahydrofuran;and (b) catalytic hydrogenation or reductive amination by sodiumcyanoborohydride or sodium triacetoxyborohydride.

Compounds of formula IC where R² is --OC(O)R¹⁴ can be prepared fromcompounds of formula IC where R² is hydroxy by treatment with an acidchloride of formula XXII in the presence of a base catalyst such aspyridine or triethylamine.

Compounds of formula XXVI are prepared by reductive amination of anamine of formula XXIII with an aldehyde of formula XXV in the presenceof a reducing agent such as sodium borohydride, sodium cyanoborohydrideand sodium triacetoxyborohydride.

Compounds of formula XXX are prepared from compounds of formula XIII bya sequence of steps which involves catalytic reduction of the doublebond followed by radical bromination.

Most of the compounds of formula XXIII, XXV, XXVII and XXIX arecommercially available or they can be prepared by standard methodsdescribed in text books of organic chemistry such as Introduction toOrganic Chemistry by A. Streitwieser and C. H. Heathcock, MacmillanPublishing Co., Inc. N.Y. (1976), and Advanced Organic Chemistry by F.C. Carey and R. J. Sundberg, Plenum Publishing Co., N.Y. (1977).

All other compounds of formula I may be prepared by modification of theprocedures discussed herein as known by those having ordinary skill inthe art. The intermediates used to prepare compounds of formula I aredescribed herein, are commercially available, or may be derived fromknown compounds by those having ordinary skill in the art or may beprepared by literature methods or derived by procedures analagous tothose described in the literature.

The compounds of the present invention can have asymmetric centers atcarbons 2-4 of the benzopyran ring. Also, any one of the R's can have anasymmetric carbon. Consequently, compounds of formula I can exist indiastereomeric forms or in mixtures thereof. The above described processcan utilize racemates, enantiomers or diastereomers as startingmaterials. When diastereomeric products are prepared, they can beseparated by conventional chromatographic or fractional crystallizationmethods.

The compounds of the formula IA wherein R⁹ and/or R¹⁰ is hydrogen, canexist as a mixture of tautomers represented by the following structures.The tautomeric products are obtained in relative amounts that differfrom compound to compound. All forms are included in the scope offormula I. ##STR34##

The compounds of the present invention can have asymmetric centers atcarbons 2-4 of the bicyclic ring. Also, any one of the R's can have anasymmetric carbon. Consequently, compounds of formula I can exist indiastereomeric forms or in mixtures thereof. The above described processcan utilize racemates, enantiomers or diastereomers as startingmaterials. When diastereomeric products are prepared, they can beseparated by methods known in the art such as conventionalchromatographic or fractional crystallization methods.

If any of the R substituents, X or Y groups contain reactive groups suchas hydroxy or amino that can interfere with the epoxide opening reactionor any other reactions, they should be protected with appropriateprotecting groups.

The compounds of formula I are unexpectedly more potent than thosedescribed previously. In addition it has been unexpectedly found thatcompounds of formula I are "selective antiischemic agents". The term"selective antiischemic agent" means that these compounds possess littleor no vasodilator activity (i.e., these compounds have IC₅₀ (rat aorta)values greater than that of the known potassium channel activator,cromakalim). Therefore, in the treatment of ischemic hearts, thecompounds of the instant invention are less likely to cause coronarysteal, profound hypotension and coronary under-perfusion.

The preferred compounds of the present invention are those compounds offormula IA and IB where:

Y is oxygen;

R² is hydroxyl;

R³ and R⁴ are methyl;

R⁶ and R⁷ are alkyl; or R⁶ and R⁷ taken together with the nitrogen atomto which they are attached form a 6-membered ring;

R⁸ is aryl or heterocyclo;

R⁹ is hydrogen;

R¹⁰ is hydrogen; and

R¹¹ is hydrogen.

Compounds of formula IC are preferred where:

X is alkyl;

Y is a single bond or --O--;

R² is hydroxy;

R³ and R⁴ are methyl;

R¹² is aryl or heterocyclo; and

R¹³ is --COOR¹⁴, --CO-amino, --CO-substituted amino, --NHCOCH₃, --NHSO₂Me, --NHCONH₂, --NH(C═NCN)NH₂, imidazole, furan, pyridine, oxazole,hydroxy, --NHCO-substituted amino or --SO₂ Me; or XR¹³ is hydrogen.

Compounds of formula I may be used as antiischemic agents, i.e., for thetreatment of ischemic conditions such as myocardial ischemia, cerebralischemia, lower limb ischemia and the like.

Thus a composition containing one (or a combination) of the compounds ofthis invention, may be administered to a species of mammal (e.g.,humans) suffering from an ischemic or hypertensive condition.

A single dose, or two to four divided daily doses, provided on a basisof about 0.001 to about 100 mg per kilogram of body weight per day,preferably about 0.1 to about 25 mg per kilogram of body weight per dayis appropriate. The substance is preferably administered orally, butparenteral routes such as the subcutaneous, intramuscular, intravenousor intraperitoneal routes or any other suitable delivery system, such asintranasal or transdermal routes can also be employed.

As a result of the potassium channel activating activity of thecompounds of this invention, these compounds are also useful in thetreatment of cardiovascular disorders and any disorders associated withsmooth muscle contraction. For example, compounds of the presentinvention are useful as therapy for congestive heart failure, therapyfor peripheral vascular disorders (e.g. Raynaud's Disease), therapy forpulmonary hypertension, as anti-anginal agents, as antifibrillatoryagents, and in limiting myocardial infarction.

Compounds of the present invention are additionally expected to beuseful in the treatment of central nervous system disorders (e.g.,Parkinsonism, as anti-tremor agents, epilepsy), in therapy for renalfailure, in therapy for urinary incontinence, as anti-diarrheal agents,in therapy for pre-eclampsia, dysmenorrhea and premature labor, for thetreatment of male impotence, as well as for the promotion of hair growth(e.g., in the treatment of male pattern baldness), and as anti-asthmaticagents.

The compounds of this invention can also be formulated in combinationwith a diuretic such as chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlothiazide, trichloromethiazide, polythiazide or benzthiazide aswell as ethacrynic acid tricrynafen, chlorthalidone, furosemide,musolimine, bumetanide, triamterene, amiloride and spironolactone andsalts of such compounds, angiotensin converting enzyme inhibitors suchas captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril,delapril, pentopril, quinapril, ramipril, lisinopril, and salts of suchcompounds, thrombolytic agents such as tissue plasminogen activator(tPA), recombinant tPA, streptokinase, urokinase, prourokinase, andanisoylated plasminogen streptokinase activator complex (APSAC, Eminase,Beecham Laboratories), or calcium channel blocking agents such asnifedipine or diltiazem. Such combination products if formulated as afixed dose employ the compounds of this invention within the dose rangedescribed above and the other pharmaceutically active agent within itsapproved dose range.

The compounds of formula I, and combinations thereof, can be formulated,as described above, in compositions such as tablets, capsules or elixirsfor oral administration, in sterile solutions or suspensions forparenteral administration, and may also be administered via transdermalpatch or nasal inhalation solutions. About 10 to about 500 milligrams ofa compound of formula I is compounded with physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, flavor,etc., in a unit dosage form as called for by accepted pharmaceuticalpractice. The amount of active substance in these compositions orpreparations is such that a suitable dosage in the range indicated isobtained.

The following examples and preparations describe the manner and processof making and using the invention and are illustrative rather thanlimiting. It should be understood that there may be other embodimentswhich fall within the spirit and scope of the invention as defined bythe claims appended hereto.

EXAMPLE 1 (3S-transs)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(diethylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR35## A. 1-Bromo-4- (1,1-dimethyl-2-propynyl)oxy!benzene ##STR36##

To a solution of 2-methyl-3-butyn-2-ol (22.3 mL, 0.23 mol) inacetonitrile (100 mL) at -2° C. (dry-ice, ice-water) was added1,8-diazabicyclo 5,4,0!undec-7-ene (DBU, 40 mL, 0.26 mol), followed bydrop-wise addition of trifluoroacetic acid anhydride (32 mL, 0.23 mol)via syringe over 30 minutes. The resultant yellow solution was stirredat 0° C. for 40 minutes. In a separate 1 L round bottomed flask, asolution of 4-bromophenol (34.6 g, 0.2 mol) in acetonitrile (150 mL) at0° C. was treated with 1,8-diazabicyclo 5,4,0!undec-7-ene (DBU, 39 mL,0.26 mol), followed by addition of 100 mg of CUCl₂. To this mixture at0° C. was added the above prepared solution via a cannula in 40 minutes.The resultant reaction mixture was stirred at 0° C. for 5 hours, and atroom temperature for 1 hour. The reaction mixture was then concentratedin vacuo and the residue was poured into water (300 mL). The aqueoussolution was extracted with a mixture of hexane and ether (300 mL, 1:1).The organic extract was washed successively with 1N HCl (200 mL), 1N KOH(2×100 mL) and saturated NaCl solution. The organic layer was then driedover MgSO₄ and concentrated to give a yellow oil (40 g, 83%).

B. 6-Bromo-2,2-dimethyl-2H-1-benzopyran ##STR37##

To 40 mL of N,N-diethylaniline at 185° C. (internal, monitored by athermal couple) was added 1-bromo-4-(1,1-dimethyl-2-propynyl)oxy!benzene (40 g, the title A compound)dropwise at such a rate that the internal temperature does not exceed195° C. (approximately 1 hour). The resultant solution was stirred at185° C. for 3 hours and poured into a mixture of hexanes (200 mL) andchilled 4% HCl (200 mL) in a beaker. The mixture was transferred to aseparatory funnel and the organic layer was separated, and washed with5% HCl (2×100 mL). The organic layer was then dried over MgSO₄ andconcentrated in vacuo to give an oil (40 g, 100%). Anal. Calc. for C₁₁H₁₁ BrO: C, 55.98; H, 4.92; Br, 32.58. Found: C, 55.95; H, 4.61; Br,32.44.

C. 2,2-Dimethyl-2H- 1 -benzopyran-6-sulfinic acid, lithium salt##STR38##

To a stirred solution of 6-bromo-2,2-dimethyl-2H-1-benzopyran (8.0 g,33.6 mmol, the title B compound) in anhydrous THF (75 mL) at -78° C.under argon was added a solution of n-BuLi in hexanes (2.5M, 15 mL, 37.5mnol) via syringe. The resultant solution was stirred at -78° C. for 30minutes and added to a solution of sulfur dioxide (35 mL, condensed at-78° C.) in anhydrous ether (150 mL) at -78° C. via a double-endedneedle. The resultant mixture was allowed to stir at -78° C. for 10minutes and allowed to warm up to room temperature over an hour. Theresultant solution was concentrated in vacuo to give a light yellowsolid which was triturated with hexanes to give the title compound as asolid (7.5 g, 91%).

D. 2,2-Dimethyl-2H-1-benzopyran-6-sulfonyl chloride ##STR39## To avigorously stirred suspension of 2,2-dimethyl-2H-1-benzopyran-6-sulfinicacid, lithium salt (7.5 g, 33 mmol, the title C compound) in hexanes(150 mL) at 0° C. under argon was added a solution of sulfuric chloride(5.0 g, 37 mmol) in hexanes (50 mL) in 3 portions over one minute. Thelight yellow suspension became a clear solution soon after addition ofthe sulfuric chloride; resulting eventually in the formation of a whiteprecipitate. The resultant suspension was stirred at 0° C. for 15minutes and the precipitate was collected. The filtrate was concentratedin vacuo to a small volume and cooled to -78° C. The precipitate thusformed was collected. The combined solid was dissolved in toluene (100mL) and the solution was washed with pH 7.0 potassium phosphate bufferfollowed by brine. The organic layer was dried over MgSO₄ andconcentrated and the residue was triturated with pentane to give a whitesolid. The mother liquor was cooled to -78° C. and the precipitate wascollected to give a solid for a total of 5.4 g (63%), mp 79°-81° C.Anal. Calc. for C₁₁ H₁₁ ClSO₃.0.13H₂ O: C, 50.61; H, 4.35; Cl, 13.58; S,12.28. Found: C, 50.61; H, 4.19; Cl, 13.80; S, 11.99.

E. N,N--Diethyl-2,2-dimethyl-2H-1-benzopyran-6-sulfonamide ##STR40##

To a stirred solution of diethylamine (1.5 g, 20.5 mmol) in a mixture ofwater and CH₂ Cl₂ (1:1; v/v; 20 mL) at 0° C., was added2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride (1.0 g, 3.9 mmol, thetitle D compound) portionwise. The resultant mixture was stirred at 0°C. for 20 minutes and room temperature for 2 hours. The organic layerwas separated and the aqueous layer was reextracted with CH₂ Cl₂ (2×50mL). The combined organic extracts were dried, concentrated in vacuo togive the title compound as an oil (1.12 g, 100%).

F. (1aS-cis)-N,N-Diethyl-1a,7b-dihydro-2,2-dimethyl-2H-oxireno c!1!benzopyran-6-sulfonamide ##STR41##

Commercial Clorox bleach (15.0 mL, 0.705M, 10.5 mmol) was diluted withNa₂ HPO₄ buffer (6 mL, 50 mM) in a single neck round-bottom flask. ThepH of the mixture was adjusted to 11.3 by addition of 1N NaOH (drops) at0° C. In a separate flask, the solution ofN,N-diethyl-2,2-dimethyl-2H-1-benzopyran-6-sulfonamide (1.1 g, 3.7 mmol,the title E compound) in CH₂ Cl₂ (15 mL) was treated with the Jacobsen'scatalyst (salem)Mn(II)! (30 mg, about 1.0 mol%, described by Lee et al,Tetrahedron Letters, 32, 5055 (1991)), followed by4-phenylpyridine-N-oxide (20 mg). This resultant solution was stirred atroom temperature for 30 minutes and at 0° C. for 30 minutes. It was thenmixed with the buffered Chlorox solution prepared above. The resultantbiphasic mixture was stirred at 0° C. for 18 hours, poured intomethylene chloride (50 mL) and the organic layer was separated. Theaqueous layer was extracted with methylene chloride (2×50 mL) and thecombined organic extracts were washed with saturated NH₄ Cl solution andbrine (25 mL each). After drying over MgSO₄, the solvent was removed invacuo to give the title F compound as an oil (1.05 g, 91%).

G.(3S-trans)-4-Amino-N,N-diethyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-sulfonamide##STR42##

To a stirred solution of(1aS-cis)-N,N-diethyl-1a,7b-dihydro-2,2-dimethyl-2H-oxireno c!1!benzopyran-6-sulfonamide (910 mg, 2.5 mmol, the title F compound) in amixture of THF and isopropanol (15 mL, 2:1, v/v) was added conc. NH₄ OH(3 mL) and the reaction mixture was heated in a sealed tube at 75° C.(oil bath temperature) for 24 hours. The reaction mixture was cooled toroom temperature and concentrated in vacuo. The residue was diluted withethyl acetate (100 mL) and extracted with saturated NaHCO₃. The organiclayer was dried, concentrated in vacuo and the residue was crystallizedfrom ethyl acetate-cyclohexane to give a white solid (850 mg, 70%).α!_(D) ²⁵ : +50.9° (c=0.90, MeOH).

H. (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(diethylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine ##STR43## To a stirred solution of(3S-trans)-4-amino-N,N-diethyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-sulfonamide(400 mg, 1.2 mmol, the title G compound) andN-chlorophenyl-N'-cyanothiourea (283 mg, 1.34 mmol) in DMF (7 mL) wasadded 1- 3-(dimethylamino)propyl!-3-ethylcarbodiimide hydrochloride (257mg, 1.34 mmol) at room temperature under argon. The reaction mixture wasstirred at room temperature for 18 hours. The resultant mixture waspoured into a mixture of ethyl acetate (100 mL) and saturated NH₄ Clsolution (50 mL). The ethyl acetate layer was separated and the aqueouslayer was reextracted with ethyl acetate (2×50 mL). The combined organiclayer was washed with brine (50 mL). After drying over MgSO₄, thesolvent was removed and the residue was purified by flash chromatography(ethyl acetate:hexane/1:1) to give a colorless solid after triturationwith ether (400 mg, 65%), mp: 125° C. (shrink); 164° C. (melts). α!_(D)²⁵ : +7.8° (c=0.60, CH₃ OH). Anal. Calc. for C₂₃ H₂₈ N₅ O₄ SCl.0.26 H₂O.0.15C₇ H₈ (toluene): C, 55.03; H, 5.71; N, 13.34; S, 6.11; Cl, 6.75.Found: C, 55.03; H, 5.64; N, 13.02; S, 5.97; Cl, 6.97.

EXAMPLE 2 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(4-piperidinylsulfonyl)-2H-1-benzopyran-4-yl!guanidine ##STR44##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 174° C.). α!_(D) ²⁵ : 18° (c=0.25, MeOH). Anal. Calc. for C₂₄H₂₈ N₅ O₄ SCl.0.20 H₂ O: C, 55.26; H, 5.49; N, 13.43. Found: C, 55.11;H, 5.47; N, 13.41.

EXAMPLE 3 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-diimethyl-6-(4-morpholinyl)sulfonyl!2H-1-benzopyran-4-yl!guanidine ##STR45## Thetitle compound was prepared by the same procedure as described for thetitle compound of Example 1. The product was obtained as a white solid(mp: 160° C.). α!_(D) ²⁵ : +27.2° (c=0.60, CH₃ OH). Anal. Calc. for C₂₃H₂₆ N₅ O₅ SCl.0.36H₂ O: C, 52.47; H, 5.12; N, 13.30; S, 6.09; Cl, 6.73.Found: C, 52.54; H, 5.23; N, 13.23; S, 5.90; Cl, 6.99. EXAMPLE 4(3S-trans)-N-(4-Chlorophenyl)-N"-cyano-N'-3,4-dihydro-3hydroxy-2,2-dimethyl-6-(phenylmethyl)amino!sulfonyl!-2H-1-benzopyran-4-yl)guanidine ##STR46##

The title compound was prepared by the same procedure as described inExample 1. The product was obtained as a white solid (mp: 140° C.).α!_(D) ²⁵ : +50.0° (c=0.40, CH₃ OH). Anal. Calc. for C₂₆ H₂₆ N₅ O₄ SCl:C, 57.83; H, 4.85; N, 12.97; S, 5.94; Cl, 6.56. Found: C, 58.18; H,4.99; N, 11.63; S, 5.86; Cl, 6.67.

EXAMPLE 5 (3S-trans )-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(cyclohexylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine ##STR47##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 165° C.). α!_(D) ²⁵ : +3.5° (c=1.3, CH₃ OH). Anal. Calc. forC₂₅ H₃₀ N₅ O₄ SCl.0.64H₂ O C, 55.24; H, 5.80; N, 12.88; S, 5.90; Cl,6.52. Found: C, 55.62; H, 5.88; N, 12.50; S, 5.64; Cl, 6.79.

EXAMPLE 6 (3S-trans)-1- 4- (4-Chlorophenyl)amino!(cyanoimino)methyl!amnino!-3,4-dihydro-3-hydroxy-1-2H-benzopyran-6-yl!sulfonyl!-2-piperidinecarboxylicacid, ethyl ester ##STR48##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 95° C.). Anal. Calc. for C₂₇ H₃₂ N₅ O₆ SCl.0.6DMF.0.5H₂ O: C,53.80; H, 5.83; N, 12.20; S, 4.99; Cl, 5.51. Found: C, 53.58; H, 5.80;N, 12.05; S, 4.82; Cl, 5.87.

EXAMPLE 7 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(phenylamino)sulfonyl!-2H-1-benzopyran-4-yl!guanidine ##STR49##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 158° C.). Anal. Calc. for C₂₅ H₂₄ N₅ O₄ SCl.1.54H₂ O: C,54.13; H, 5.10; N, 12.63; S, 5.78; Cl, 6.39. Found: C, 54.57; H, 4.86;N, 12.19; S, 5.59; Cl, 7.88.

EXAMPLE 8 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- 2- (phenylmethyl)-1-piperidinyl)sulfonyl!-2H-1 benzopyran-4-yl!guanidine ##STR50##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 105° C.). Anal. Calc. for C₃₁ H₃₄ N₅ O₄ SCl.0.70H₂ O.0.40DMF:C, 59.50; H, 5.92; N, 11.64; S, 4.93; Cl, 5.45. Found: C, 59.53; H,6.05; N, 11.95; S, 4.70; Cl, 5.17.

EXAMPLE 9 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(2-phenyl-1-piperidinyl)sulfonyl!-2H-1 -benzopyran-4-yl!guanidine##STR51##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 143° C.). Anal. Calc. for C₃₀ H₃₂ N₅ O₄ SCl.0.26H₂ O: C,60.17; H, 5.47; N, 11.69; S, 5.35; Cl, 5.92. Found: C, 59.89; H, 5.77;N, 11.95; S, 5.41; Cl, 5.49.

EXAMPLE 10 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-4-(phenylmethyl)-1-piperidinyl!-sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR52##

The title compound was prepared by the same procedure as employed forthe preparation of the Example 1 by using 4-benzylpiperidine fordiethylamine. The title compound was obtained as a white solid(mp: >200° C.). Anal. Calc. for C₃₁ H₃₄ N₅ O₄ SCl: C, 61.22; H, 5.63; N,11.52; S, 5.27; Cl, 5.83. Found: C, 61.07; H, 5.64; N, 11.36; S, 5.19;Cl, 5.88.

EXAMPLE 11 (3S-trans)-1- 4-(4-Chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!-N-ethyl-2-piperidine-carboxamide##STR53##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid mp: 170° C. (foams)!. Anal. Calc. for C₂₇ H₃₃ N₆ ClSO₅ : C, 55.05;H, 5.65; N, 14.27; Cl, 6.02; S, 5.49. Found: C, 55.07; H, 5.81; N,14.08; Cl, 6.36; S, 5.44.

EXAMPLE 12 (3S-trans)- N- 4-(4-Chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!phenylamino!aceticacid, ethyl ester ##STR54##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a lightyellow solid (mp: 158° C.). Anal. Calc. for C₂₉ H₃₀ N₅ O₆ SCl.0.37H₂ O:C, 56.29; H, 5.01; N, 11.32; S, 5.18; Cl, 5.73. Found: C, 56.47; H,4.99; N, 11.14; S, 5.46; Cl, 6.16.

EXAMPLE 13 (3S-trans)-N-(3-Chlorophenyl)-N'- 6-(diethylamino)-sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!urea##STR55##

To a stirred solution of the title G compound of Example 1 (148 mg, 0.45mmol) in 10 mL of CH₂ Cl₂ in the presence of 1 mL of saturated NaHCO₃,was added 3-chlorophenyl-isocyanate (70 mL, 0.53 mmol) at 0° C. Thereaction mixture was allowed to stir at 0° C. for 10 minutes. Work upwith 10% aqueous KOH solution gave the title compound as a crystallinesolid (135 mg, 62%, mp: 202°-203° C.). Anal. Calc. for C₂₂ H₂₈ N₃ O₅SCl: C, 54.82; H, 5.86; N, 8.72; S, 6.65. Found: C, 54.40; H, 5.90; N,8.59; S, 6.53.

EXAMPLE 14 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(2-ethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR56##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a tan solid(mp: 158° C.). Anal. Calc. for C₂₆ H₃₂ N₅ O₄ SCl.0.45H₂ O: C, 56.35; H,5.98; N, 12.64; S, 5.79; Cl, 6.40. Found: C, 56.68; H, 6.12; N, 12.29;S, 5.90; Cl, 6.49.

EXAMPLE 15(7S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-(3,6,7,8-tetrahydro-7-hydroxy-6,6-dimethyl-2-phenyl-2H-pyrano-2,3-f!-benzisothiazol-8-yl)guanidine, 1,1-dioxide ##STR57##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 230°-232° C.). Anal. Calc. for C₂₆ H₂₄ N₅ O₄ SCl.0.44H₂ O: C,57.20; H, 4.59; N, 12.83; Cl, 6.49; S, 5.87. Found: C, 57.32; H, 4.21;N, 12.70; Cl, 6.67; S, 5.83.

EXAMPLE 16 trans-N-(4-Chlorophenyl)-N'-cyano-N"-N-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(3-pyridinylamino)sulfonyl!-2H-1-benzopyran-4-yl!guanidine ##STR58##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a lightyellow solid (mp: 165° C.). Anal. Calc. for C₂₄ H₂₃ N₆ O₄ SCl.0.39H₂ O:C, 53.98; H, 4.49; N, 15.74. Found: C, 53.98; H, 4.21; N, 15.75.

EXAMPLE 17 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-N-3,4-dihydro-3-hydroxy-2,2- dimethyl-6- (2-phenylethyl)(3-pyridinylmethyl)amino!sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR59##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 110° C.). Anal. Calc. for C₃₃ H₃₃ N₆ O₄ SCl.0.4H₂ O: C,60.75; H, 5.22; N, 12.89; S, 4.91; Cl, 5.43. Found: C, 61.00; H, 5.00;N, 12.29; S, 5.14; Cl, 5.77.

EXAMPLE 18 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-N- 6-(2,2-dimethylpropyl) (2-phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR60##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 143° C.). Anal. Calc. for C₃₂ H₃₈ N₅ O₄ SCl: C, 61.58; H,6.14; N, 11.22; S, 5.14; Cl, 5.68. Found: C, 61.54; H, 6.30; N, 11.02;S, 5.07; Cl, 5.48.

EXAMPLE 19 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-ethyl(2-phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H1-benzopyran-4-yl!guanidine ##STR61##

The title compound was prepared by the same procedure as employed forthe preparation of the Example 1 by using ethyl 2-phenylethyl amine fordiethylamine. The title compound was obtained as a white solid (mp:127°-131° C.). Anal. Calc. for C₂₉ H₃₂ N₅ O₄ SCl: C, 59.86; H, 5.54; N,12.03; S, 5.51; Cl, 6.09. Found: C, 60.05; H, 5.69; N, 11.64; S, 5.32;Cl, 5.84.

EXAMPLE 20 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 3,4-dihydro-3.hydroxy-2,2-dimethyl-6-(3-methyl-1-piperidinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR62##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 175° C.). Anal. Calc. for C₂₅ H₃₀ N₅ O₄ SCl.0.52H₂ O C,55.46; H, 5.78; N, 12.94; S, 5.92; Cl, 6.55. Found: C, 55.57; H, 5.69;N, 12.66; S, 5.86; Cl, 6.56.

EXAMPLE 21 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(3,3-dimethyl-1-piperidinyl)-sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR63##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 175° C.). Anal. Calc. for C₂₆ H₃₂ N₅ O₄ SCl.0.31H₂ O C,55.61; H, 5.96; N, 12.70; S, 5.81; Cl, 6.43. Found: C, 57.04; H, 6.01;N, 12.27; S, 5.75; Cl, 6.23.

EXAMPLE 22 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1-pyrrolidinylsulfonyl)-2H-1-benzopyran-4-yl!guanidine##STR64##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 127°-131° C.). α!_(D) =+7.4° (c=0.7, MeOH). Anal. Calc. forC₂₃ H₂₆ N₅ ClSO₄ 1.8 H₂ O.0.11 CHCl₃ : C, 50.49; H, 5.49; N, 12.74; S,5.83; Cl, 8.58. Found: C, 50.20; H, 5.24; N, 13.10; S, 5.65; Cl, 8.99.

EXAMPLE 23 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(hexahydro-1H-azepin-1-yl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR65##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 157°-161° C.). α!_(D) =+1.1° (c=0.4, MeOH). Anal. Calc. forC₂₅ H₃₀ N₅ ClSO₄. 0.85 H₂ O.0.09 CHCl₃ : C, 53.98; H, 5.77; N, 12.54; S,5.74; Cl, 8.06. Found: C, 54.36; H, 5.62; N, 12.04; S, 5.71; Cl, 7.67.

EXAMPLE 24 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(ethylphenyl-amino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR66##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 115°-119° C.). α!_(D) =-11.1° (c=0.7, MeOH). Anal. Calc. forC₂₇ H₂₈ N₅ ClSO₄.0.7 H₂ O.0.05 CHCl₃ : C, 53.98; H, 5.77; N, 12.54; S,5.74; Cl, 8.06. Found: C, 54.36; H, 5.62; N, 12.04; S, 5.71; Cl, 7.67.

EXAMPLE 25 (3S-trans)-1- 4-(4-Chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-1-2-benzopyran-6-yl!sulfonyl!-3-piperidinecarboxylicacid, ethyl ester ##STR67##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 158°-160° C.). α!_(D) =+6.9°, (c=0.6, MeOH). Anal. Calc. forC₂₇ H₃₂ N₅ ClSO₆.0.25H₂ O.0.33 CHCl₃ : C, 51.72; H, 5.32; N, 11.03; S,5.05; Cl, 11.12. Found: C, 51.89; H, 5.04; N, 10.64; S, 5.29; Cl, 11.22.

EXAMPLE 26 (3S-trans)-4- 4-(4-Chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-1-2H-benzopyran-6-yl!sulfonyl!-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester ##STR68##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 128°-132° C.). α!_(D) =+11.3° (c=0.6, MeOH). Anal. Calc. forC₂₈ H₃₅ N₆ O₆ SCl.0.95 H₂ O: C, 52.86; H, 5.83; N, 13.21. Found: C,52.83; H, 5.80; N, 13.23.

EXAMPLE 27 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(4-methyl-1-piperidinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR69##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 157°-160° C.). α!_(D) =+12.7° (c=0.3, MeOH). Anal. Calc. forC₂₅ H₃₀ N₅ O₄ SCl.0.35 H₂ O: C, 55.37; H, 5.70; N, 12.89; S, 5.90; Cl,7.31. Found: C, 55.37; H, 5.61; N, 12.79; S, 5.77; Cl, 7.53.

EXAMPLE 28 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(2-phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR70##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 125°-130° C.). α!_(D) =+27.9° (c=0.3, MeOH). Anal. Calc. forC₂₉ H₂₉ N₆ O₄ SCl.0.4 H₂ O.0.24 CF₃ CO₂ H: C, 56.41; H, 4.82; N, 13.39;S, 5.11; Cl, 5.65; F, 2.19. Found: C, 56.35; H, 4.65; N, 13.64; S, 4.84;Cl, 5.33, F, 2.14.

EXAMPLE 29 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(phenylmethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR71##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 153°-155° C.). α!_(D) =+60.0° (c=0.3, MeOH). Anal. Calc. forC₂₈ H₂₇ N₆ O₄ SCl.0.7 H₂ O.0.05 CHCl₃ : C, 56.37; H, 4.80; N, 14.06; S,5.36; Cl, 6.82. Found: C, 56.59; H, 4.59; N, 13.86; S, 5.20; Cl, 6.50.

EXAMPLE 30 (3S-trans)-N- 6-Bis(phenylmethyl)amino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine##STR72##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 199°-201° C.). α!_(D) =+68.0° (c=0.5, MeOH). Anal. Calc. forC₃₃ H₃₂ N₅ O₄ SCl.0.1 H₂ O.0.05 CHCl₃ : C, 62.23; H, 5.10; N, 10.98; S,5.03; Cl, 6.39. Found: C, 62.46; H, 4.85; N, 10.84; S, 4.93; Cl, 6.39.

EXAMPLE 31 3S- 3a,4b,6(cis)!!-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(2,6-dimethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR73##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 176°-178° C.). α!_(D) =-15.0° (c=0.4, MeOH). Anal. Calc. forC2₆ H₃ 2N₅ O₄ SCl.0.3 H2O.0.25 CHCl₃.0.1 EtOAc: C, 54.24; H, 5.75; N,11.87. Found: C, 54.60; H, 5.37; N, 11.51.

EXAMPLE 32 (3S-trans)-N- 6- Bis(2-methylpropyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine##STR74##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 145°-148° C.). α!_(D) =-0.5° (c=0.36, MeOH). Anal. Calc. forC₂₇ H₃₆ N₅ O₄ SCl.0.9 H₂ O: C, 56.08; H, 6.59; N, 12.11. Found: C,56.42; H, 6.36; N, 11.76.

EXAMPLE 33 (3S-- trans)-N-(4-Chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(3-phenylpropyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine##STR75## The title compound was prepared by the same procedure asdescribed for the title compound of Example 1. The product was obtainedas a white solid (mp: 99°-101° C.). α!_(D) =+20.0° (c=0.31, MeOH). Anal.Calc. for C₃₀ H₃₁ N₆ ClSO₄.1.0 H₂ O.0.10 CHCl₃ : C, 56.75; H, 5.24; N,13.19; S, 5.03; Cl, 7.23. Found: C, 56.75; H, 5.32; N, 13.38; S, 4.75;Cl, 7.27. EXAMPLE 34 N-(4-Chlorophenyl)-N'-cyano-N"- (3S,4R)-6-(3,5-dimethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2dimethyl-2H-1-benzopyran-4-yl!guanidine ##STR76##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 138°-140° C.). α!_(D) =-4.0° (c=0.36, MeOH). Anal. Calc. forC₂₆ H₃₂ N₅ SClO₄.1.70 H₂ O.0.10 CHCl₃ : C, 53.26; H, 6.08; N, 11.90; S,5.45; Cl, 7.83. Found: C, 53.66; H, 5.77; N, 12.14; S, 5.02; Cl, 7.93.

EXAMPLE 35 N-(4-Chlorophenyl)-N'-cyano-N"-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- 3-(phenylmethyl)-1-piperidinyl)-sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR77##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 150° C.). Anal. Calc. for C3lH₃₄ N₅ O₄ SCl: C, 61.22; H,5.63; N, 11.52; S, 5.27; Cl, 5.83. Found: C, 61.21; H, 5.66; N, 11.14;S, 5.12; Cl, 6.19.

EXAMPLE 36 (3S-trans)-1- 4-(Cyclohexylamnino)carbonyl!amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-1-2H-benzopyran-6-yl!sulfonyl!-2-piperidinecarboxylicacid, ethyl ester ##STR78##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 110° C.). Anal. Calc. for C₂₆ H₃₉ N₃ O₇ S: C, 58.08; H, 7.31;N, 7.86; S, 5.96. Found: C, 57.92; H, 7.46; N, 7.46; S, 5.86.

EXAMPLE 37 (3S-trans)-1- 3,4-Dihydro-3-hydroxy-2,2-dimethyl-4-(phenylmethyl)amino!carbonyl!amino!-1-2H-benzopyran-6-yl)sulfonyl!-2-piperidinecarboxylicacid, ethyl ester ##STR79##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a whitesolid (mp: 105° C.). Anal. Calc. for C₂₇ H₃₅ N₃ 0₇ S: C, 59.43; H, 6.47;N, 7.70; S, 5.88. Found: C, 57.06; H, 6.49; N, 7.49; S, 5.99.

EXAMPLE 38 (3S-trans)-1- 3,4-Dihydro-3-hydroxy-2,2-dimethyl-4-(2-thiazolylamino)carbonyl!amino!-1-2H-benzopyran-6-yl!sulfonyl!-2-piperidinecarboxylicacid, ethyl ester ##STR80##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was obtained as a yellowsolid (mp: 102° C.). Anal. Calc. for C₂₃ H₃₀ N₄ O₇ S₂ 0.45C₇ H₈ : C,54.14; H, 5.84; N, 9.66; S, 11.05. Found: C, 54.20; H, 5.85; N, 9.35; S,10.73.

EXAMPLE 39 (3S-trans)-N- 6- (3-Azabicyclo3.2.2!nonan-3-yl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine##STR81##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was triturated with hotethyl acetate/hexanes (1:1), mp 213°-216° C. α!_(D) =+7.6° (c=0.42,MeOH). Anal. Calc. for C₂₆ H₂₂ CIN₅ O₃. 0.40H₂ O: C, 57.36; H, 5.85; N,12.39; S, 5.67; Cl, 6.27. Found: C, 57.77; H, 5.80; N, 11.98; S, 5.68;Cl, 6.26. m/s, MH+@ 488, MW=487.

EXAMPLE 40 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- (1,2,3,4-tetrahydro-1-quinolinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR82##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was triturated with ethylether/hexanes to provide the title compound, as a colorless solid; mp155°-158° C. α!_(D) ²⁵ =+168.0° (c=0.44, CHCl₃). Anal. Calc. for C₂₇ H₂₆N₅ C1SO₄.0.31 H₂ O: C, 58.15; H, 4.81; N, 12.56; Cl, 6.36; S, 5.75.Found: C, 58.39; H, 4.65; N, 12.32; Cl, 5.91; S, 5.81.

EXAMPLE 41 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1,2,3,4-tetrahydro-2-isoquinolinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR83##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was triturated with ethylether and hexanes to provide the title compound, as a colorless solid;mp 182°-185° C. (foaming, started @ 160° C.). α!_(D) ²⁵ =+212.3°(c=0.483, CHCl₃). Anal. Calc. for C₂₈ H₂₈ N₅ ClSO₄ : C, 59.41; H, 4.99;N, 12.37; Cl, 6.26; S, 5.66. Found: C, 59.34; H, 4.88; N, 11.93; Cl,5.34; S, 5.52.

EXAMPLE 42 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(octahydro-1-quinolinyl)-sulfonyl!-2H-1-benzopyran-4-yl!guanidine##STR84##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was triturated with ethylether and hexanes to provide the title compound, as a colorless solid;mp 188°-190° C. (foaming, started @ 168° C.). α!_(D) ²⁵ =+183.4°(c=0.325, CHCl₃). Anal. Calc. for C₂₈ H₂₈ N₅ ClSO₄.0.12 C₄ H₁₀ O. 0.2 H₂O: C, 58.51; H, 6.14; N, 11.98; Cl, 6.06; S, 5.48. Found: C, 58.52; H,6.44; N, 11.56; Cl, 5.68; S, 5.17.

EXAMPLE 43 (3S-trans)-N-(4-Chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(4-thiamorpholinylsulfonyl)-2H-1-benzopyran-4-yl!guanidine,1,1-dioxide ##STR85##

The title compound was prepared by the same procedure as described forthe title compound of Example 1. The product was triturated with ethylether and hexanes to provide the title compound as a colorless solid; mp185°-187° C. α!_(D) ²⁵ =+157.6° (c=0.25, CHCl₃). Anal. Calc. for C₂₃ H₂₆N₅ ClS₂ O₆.0.08 C₄ H₁₀ O. 0.1 H₂ O: C, 48.65; H, 4.73; N, 12.16; Cl,6.16; S, 11.14. Found: C, 48.65; H, 4.58; N, 11.80; Cl, 6.30; S, 10.69.

EXAMPLE 44 (3R-trans)-1- 4-4-Chloro-N-(1H-imidazol-2-yl-methyl)-phenylamino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H1-benzopyran-6yl!sulfonyl!piperidine, monohydrochloride ##STR86## A.N-(4-Chlorophenyl)-N- (1H-imidazol-2-yl)methyl!-amine ##STR87##

A mixture of 4-chloroaniline (66.65 g, 522.43 mmol) and2-imidazolecarboxaldehyde (50.2 g, 522.43 mmol) in methanol (1000 mL)was stirred at 55°-60° C. overnight. The light brown reaction mixturewas cooled in an ice bath and treated with sodium borohydride (21.74 g,574.67 mrnol) in small portions. The reaction mixture was allowed towarm to room temperature and stirred for 2 hours. It was concentratedand partitioned between water (˜500 nmL) and ethyl acetate (1200 mL),giving a white solid/aqueous layer and a brown organic layer. Theorganic layer was removed and the aqueous mixture was reextracted withethyl acetate (3×200 mL). The combined organic layers were washed withbrine, dried over sodium sulfate and concentrated. The resulting mixturewas treated with hexanes and stored in the freezer for 2 hours. Thewhite solid was collected by filtration and washed with cold ethylacetate/hexane (2:1) to provide the title product (83.36 g, 77%) as awhite solid, mp 163°-165° C. Anal. Calc. for C₁₀ H₁₀ ClN₃ : C, 57.84; H,4.85; N, 20.23; Cl, 17.07. Found: C, 57.82; H, 4.85; N, 20.04; Cl,16.77.

B. (1aR-cis)-1- (1a,7b-Dihydro-2,2-dimethyl-2H-oxireno 1!-c!benzopyran-6-yl)sulfonyl!piperidine ##STR88##

The title compound was prepared from the corresponding olefin (sameprocedure as described for the title E compound of Example 1) by theprocedure of Lee et al, Tetrahedron Letters, 32, 5055 (1991), asdescribed in the preparation of the title F compound of Example 1.

C. (3R-trans)-1- 4-4-Chloro-N-(1H-imidazol-2-yl-methyl)-phenylamino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-11-benzopyran-6-yl!sulfonyl!piperidine,monohydrochloride

A solution of the title B compound (890 mg, 2.75 mmol) in acetonitrile(3 mL) was treated with the title A compound (572 mg, 2.75 mmol) andcobalt chloride (355 mg, 2.75 mmol). The reaction mixture was heated at80° C. under argon for 2 hours and then at 60° C. for 18 hours. Theblue-green solution was partitioned between ethyl acetate (100 mL) andwater (100 mL) and the organic fraction was washed with brine (100 mL),dried (MgSO4), filtered through a plug of silica gel on celite and thesolvent was removed to give a green oil. The residue was purified onsilica gel using EtOAc/Hexane (40:60) to give a yellow oil. The oil wascrystallized from dichloromethanehexanes to give a light yellow solid(340 mg, 23%) which in THF/MeOH (3:2, 4 mL) was converted to itshydrochloride salt by treatment with ethereal-HCl. The solvent wasremoved and the residue was triturated with hexanes to give a paleyellow solid (380 mg, 20%), mp 164° C. (softens at 170° C.). α!_(D)=+18.10° (c=0.37, MeOH). Anal. Calc. for C₂₆ H₃₁ ClN₄ O₄ S.1.00 HCl.1.08H2O.0.17 Hexane: C, 53.94; H, 6.12; N, 9.31; Cl, 11.79; S, 5.33. Found:C, 53.95; H, 6.00; N, 8.87; Cl, 12.00; S, 4.91.

EXAMPLE 45 (3S-trans)-1- 4-4-Chloro-N-(1H-imidazol-2-yl-methyl)-phenylamino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!piperidine,monohydrochloride ##STR89## A. (1aS-cis)-1-(1a,7b-Dihydro-2,2-dimethyl-2H-oxireno 1!c!benzopyran-6-yl)sulfonyl!piperidine ##STR90##

The title compound was prepared from the corresponding olefin (sameprocedure as described for title E compound of Example 1) by theprocedure of Lee et al, Tetrahedron Letters, 32, 5055 (1991) asdescribed in the preparation of the title F compound of Example 1.

B. (3S-trans)-1- 4-4-Chloro-N-(1H-imiidazol-2-yl-methyl)-phenylamino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!piperidine,monohydrochloride

The title compound was prepared from the title A compound ((1aS-cis)-1-(1a,7b-dihydro-2,2-dimethyl-2H-oxireno 1!c!benzopyran-6-yl)sulfonyl!piperidine) and title A compound of Example44 (N-(4-chlorophenyl)-N- (1H-imidazol-2-yl)methyl!amine) by the sameprocedure as described for the title compound of Example 44. mp 164° C.(softens at 170° C.). α!_(D) =-27.4° (c=0.5, MeOH). Anal. Calc. for C₂₆H₃₁ ClN₄ O₄ S.1.0 HCl.0.63 H2O.0.16 THF: C, 54.50; H, 5.92; N, 9.54; Cl,12.08; S, 5.46. Found: C, 54.43; H, 5.63; N, 9.17; Cl, 12.23; S, 5.86.

EXAMPLE 46 (3R-trans)- N-3,4-Dihydro-3-hydroxy-2,2-dimethyl-6-(1-piperidinylsulfonyl)-2H-1-benzopyran-4-yl!phenylamino!-aceticacid, ethyl ester ##STR91##

A solution of the title B compound of Example 44 (400 mg, 1.24 mmol) inCH₃ CN (500 μL) was treated with magnesium perchlorate (414 mg, 1.86mmol) and N-phenylglycine ethyl ester (243 mg, 1.36 mmol). The solutionwas stirred at room temperature under argon for 18 hours, during whichtime the solution solidified. The reaction mixture was taken up in ethylacetate (100 mL) and diluted with water (100 mL). The organic layer wasseparated and washed with NaHCO₃ solution, brine and dried over MgSO₄.The solvent was removed and the residue was purified by flashchromatography on silica gel using EtOAc:hexane (40:60) to give a whitefoam (340 mg, 80%), mp 95°-96.5° C. α!_(D) =+151.5° (c=0.40, MeOH).Anal. Calc. for C₂₆ H₃₄ N₂ O₆ S.0.29 H₂ O: C, 61.49; H, 6.86; N, 5.52;S, 6.31. Found: C, 61.57; H, 6.82; N, 5.44; S, 6.40.

EXAMPLE 47 (3S-trans)-4-(4-Chlorophenyl)(1H-imidazol-2-ylmethyl)-amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-N,N-bis(2-methylpropyl)-2H-1-benzopyran-6-sulfonamide##STR92## A. (1aS-cis)-1-(1a,7b-dihydro-2,2-dimethyl-2,2-dimethyl-2H-oxireno 1! -c!benzopyran-6-yl)-N,N-bis(2-methylpropyl)sulfonamide ##STR93##

The title compound was prepared from the corresponding olefin (sameprocedure as described for the title E compound of Example 1) by theprocedure of Lee et al, Tetrahedron Letters, 32, 5055 (1991), asdescribed in the preparation of the title F compound of Example 1.

B. (3S-trans)-4-(4-Chlorophenyl)(1H-imidazol-2-ylmethyl)-amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-N,N-bis(2-methylpropyl) -2H-1-benzopyran-6-sulfonamide.

A solution of the N-(4-chlorophenyl)-N- (1H-imidazol-2-yl)methyl!amine(445 mg, 2.14 inmol, the title A compound of Example 44) in dry THF (2.5mL), was cooled to -78° C. and treated with 2.5M n-butyllithium inhexanes (1.7 ml, 4.28 mmol). The solution was allowed to warm to -25° C.and stirred for 0.5 hours then cooled back to -78° C. A solution of thetitle A compound (785 mg, 2.14 mmol) in THF was added via syringe. Thesolution was stirred overnight under argon while warming to r.t. Thesolution was partitioned between ethyl acetate and (sat,.aq.) NaHCO₃solution. The organic fraction was washed with brine, dried over MgSO₄,filtered and solvent was removed in vacuo to give a brown gum. Theresidue was purified on silica gel using 40:60/ethy acetate:hexane togive the title compound as a white solid (254 mg, 21%), mp 214°-216° C.(discoloration @ 185° C.). α!_(D) =-37.5°, (c=0.64, MeOH). Analysiscalculated for C₂₉ H₃₉ ClN₄ O₄ S: C, 60.56, H, 6.83, N, 9.74, Cl, 6.16,S, 5.57. Found: C, 60.46, H, 6.93, N, 9.51, Cl, 5.87, S, 5.55.

Using the procedures described herein or by modification of theprocedures described herein as known by one having ordinary skill in theart, the following additional compounds were also prepared.

      - Example Structure M.P. 0° C. (solvent) Rotation (α.sub.D     °) Analysis      48      ##STR94##      189 (foaming) racemate Calculated for C.sub.19 H.sub.21 N.sub.5 O.sub.4     SCl.0.34 H.sub.2 O: C,50.04; H, 4.57; N, 15.35; Cl, 7.77; S, 7.03.Found:     C, 50.33; H, 4.88; N, 15.06; Cl, 7.89; S,6.66.     49      ##STR95##      128-134 +30.8 (c = 0.52, MeOH) Calculated for C.sub.30 H.sub.34 N.sub.5     O.sub.4 SCl.0.83 H.sub.2 O: C,60.44; H, 5.75; N, 11.75; Cl, 5.95; S,     5.38.Found: C, 59.10; H, 5.87; N, 11.49; Cl, 5.82; S,5.26.     50      ##STR96##      122-132 +6.6 (c = 0.65, MeOH) Calculated for C.sub.23 H.sub.25 N.sub.5     O.sub.4 F.sub.3 SCl.0.26 H.sub.2 O:C, 60.92; H, 6.10; N, 11.46; Cl,     5.80; S, 5.25.Found: C, 60.56; H, 5.99; N, 11.39; Cl, 5.77; S,5.21.                                                                         51      ##STR97##      130-140 +153 (c = 0.23, CHCl.sub.3) Calculated for C.sub.23 H.sub.25     N.sub.5 O.sub.4 F.sub.3 SCl.0.03C.sub.6 H.sub.14 : C, 49.50; H, 4.56; N,     12.45; Cl, 6.30;S, 5.70.Found: C, 49.89; H, 4.38; N, 12.12; Cl, 6.44;     S,5.52.     52      ##STR98##      160-163 (softens @ 142) -21.8 (c = 0.51, MeOH) Calculated for C.sub.20     H.sub.26 N.sub.4 O.sub.5 S.sub.2.0.3 EtOAc: C,51.65; H, 5.81; N, 11.36;     S, 13.01.Found: C, 52.00; H, 6.03; N, 10.99; S, 12.71.     53      ##STR99##      152-155 +148.1 (c = 0.27, CHCl.sub.3) Calculated for C.sub.23 H.sub.22     N.sub.5 O.sub.4 F.sub.6 SCl: C, 45.0; H,3.61; N, 11.41; Cl, 5.77; S,     5.22.Found: C, 45.24; H, 3.66; N, 11.53; Cl, 6.46; S,4.78.     54      ##STR100##      165-168 (foams) +183.4 (c = 0.46, CHCl.sub.3) Calculated for C.sub.28     H.sub.28 N.sub.5 O.sub.4 SCl.0.31 H.sub.2 O: C,58.82; H, 5.05; N,     12.25.Found: C, 59.13; H, 4.95; N, 11.94.     55      ##STR101##      155  Calculated for C.sub.24 H.sub.23 N.sub.6 O.sub.4 SCl.0.39 H.sub.2     O: C,53.98; H, 4.49; N, 15.74.Found: C, 53.98; H, 4.21; N, 14.75                                                                      56      ##STR102##      120-122  Calculated for C.sub.23 H.sub.34 N.sub.4 O.sub.5      S.sub.2.0.5H.sub.2 O: C,53.15; H, 6.79; N, 10.78; S, 12.34.Found: C,     53.07; H, 6.97; N, 10.52; S, 12.02.     57      ##STR103##      88-91 +30.0 Calculated for C.sub.30 H.sub.31 N.sub.6 O.sub.4      SCl.1.30H.sub.2 O: C,57.15; H, 5.37; N, 13.33; Cl, 5.62; S, 5.08.Found:     C, 57.13; H, 5.52; N, 13.52; Cl, 5.71; S,4.95.     58      ##STR104##      142-144 -1.7 (c = 0.5, MeOH) Calculated for C.sub.24 H.sub.30 N.sub.5     O.sub.4 SCl.0.2H.sub.2 O.0.2CHCl.sub.3 : C, 53.09;H, 5.63; N, 12.78; Cl,     10.36; S, 5.86.Found: C, 53.07; H, 5.58; N, 12.42; Cl, 10.17;S, 6.16.                                                                           59      ##STR105##      150 (softens)  Calculated for C.sub.25 H.sub.32 N.sub.5 O.sub.4 SCl: C,     56.22; H,6.04; N, 13.11; Cl, 6.64; S, 6.00.Found: C, 56.14; H, 6.04; N,     12.80; Cl, 6.93; S,5.87.     60      ##STR106##      95-97 +57.5 (c = 0.5, MeOH) Calculated for C.sub.27 H.sub.35 N.sub.3     O.sub.5 S.0.2H.sub.2 O: C,62.21; H, 7.62; N, 8.06; S, 6.15.Found: C,     62.01; H, 7.60; N, 7.86; S, 6.07.     61      ##STR107##      90 (softens) -10.4 (c = 0.5, MeOH) Calculated for C.sub.25 H.sub.27     N.sub.5 O.sub.5 S.sub.2 : C, 55.44; H,5.02; N, 12.93; S, 11.84.Found: C,     55.11; H, 5.05; N, 12.98; S,11.86.     62      ##STR108##      184-186  Calculated for C.sub.26 H.sub.37 N.sub.3 O.sub.5 S: C, 62.00;     H,7.40; N, 8.34; S, 6.37.Found: C, 62.35; H, 7.42: N, 8.33; S, 6.10.                                                                          63      ##STR109##      210-212  Calculated for C.sub.25 H.sub.36 N.sub.4 O.sub.5 S: C, 59.50;     H,7.19; N, 11.10; S, 6.35.Found: C, 59.28; H, 7.24: N, 10.93; S, 6.29.     64      ##STR110##      155-158 -6.5 (c = 0.3, MeOH) Calculated for C.sub.24 H.sub.30 N.sub.5     O.sub.4 SCl.0.50H.sub.2 O.0.25CHCl.sub.3 : C, 52.11; H, 5.62; N,     12.53;Cl, 11.10; S, 5.74.Found: C, 52.03; H, 5.54; N, 12.42; Cl,     10.93;S, 5.74.     65      ##STR111##      125-128 -43 (c = 0.3, MeOH) Calculated for C.sub.20 H.sub.28 N.sub.4     O.sub.5 S.sub.2.0.50C.sub.3 H.sub.7 NO.0.5CHCl.sub.3 : C,46.78; H, 5.71;     N, 11.17; S, 11.35.Found: C, 47.11; H, 5.47; N, 10.90; Cl, 10.04.                                                                       66      ##STR112##      127-129 -12.4 (c = 0.42, MeOH) Calculated for C.sub.35 H.sub.42 N.sub.3     O.sub.6 SCl.0.63 H.sub.2 O: C,61.86; H, 6.42; N, 6.18; Cl, 5.22; S,      F     4.72.ound: C, 62.21; H, 6.42: N, 5.84; Cl, 5.35; S,4.72.     67      ##STR113##      >175 (decomposition) +27.8 (c = 0.4, DMSO) Calculated for C.sub.27     H.sub.34 N.sub.3 O.sub.5 SCl.1.1 H.sub.2 O.0.1EtOAc: C, 57.49; H, 6.20;     N, 6.87; Cl, 6.42.Found: C, 57.46; H, 6.20; N, 6.91; Cl, 6.42.     68      ##STR114##      230-231 ((softens @ 195) +7.2 (c = 0.33, MeOH) Calculated for C.sub.27     H.sub.33 N.sub.4 O.sub.4 SCl.0.7H.sub.2 O.0.27EtOAc: C, 59.49; H, 5.99;     N, 10.15;Cl, 6.50; S, 5.88.Found: C, 59.09; H, 6.10; N, 10.28; Cl, 6.76;     S,5.66.     69      ##STR115##      138-140 +85.5 (c = 0.22, MeOH) Calculated for C.sub.28 H.sub.37 N.sub.3     O.sub.4 S.sub.2 : C, 661.85; H,6.86; N, 7.73; S, 11.79.Found: C, 62.08;     H, 6.80 N, 7.55; S, 11.99.     70      ##STR116##      138-140 (softens 130) -74.4 (c = 0.25, MeOH) Calculated for C.sub.28     H.sub.37 N.sub.3 O.sub.4 S.sub.2 : C, 661.85; H,6.86; N, 7.73; S,     11.79.Found: C, 61.83; H, 6.97; N, 7.46; S, 11.70.

What is claimed is:
 1. A compound of the formula ##STR117## or apharmaceutically acceptable salt thereof wherein R¹ is ##STR118## R² ishydrogen, hydroxy, or --OC(O)R¹⁴ ; R³ and R⁴ are each independentlyhydrogen, alkyl or arylalkyl; or R³ and R⁴ taken together with thecarbon atom to which they are attached form a 3- to 7-memberedcarbocyclic ring;R⁵ is hydrogen, alkyl, halogen, heterocyclo, nitrile,haloalkyl or aryl; R⁶ and R⁷ are independently hydrogen, alkyl,cycloalkyl, aryl, arylalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylsubstituted with a carboxylic ester or carboxylic acid, alkoxyalkyl,thioalkyl, (cycloalkyl)alkyl, morpholinylalkyl, heterocyclo or(heterocyclo) alkyl; or R⁶ and R⁷ taken together with the nitrogen atomto which they are attached form a 5- to 7-membered mono or bicyclic ringincluding a fused ring which is 1-pyrrolidinyl, 1-piperidinyl,1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 4-thiamorpholine dioxide,1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl,4-diarylalkyl-1-piperazinyl; or 1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl or 1-azepinyl substituted with one or more alkyl, alkoxy,alkylthio, halo, trifluoromethyl, hydroxy, aryl, arylalkyl, --COOR¹⁴ or--CO--substituted amino; or R⁵ and R⁶ taken together with the atoms towhich they are attached form a 5- to 7-membered ring which contains twohetero atoms optionally substituted with aryl; R⁸ is aryl; R⁹ ishydrogen or alkyl; R¹⁰ and R¹¹ are independently hydrogen, alkyl,alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl; or R¹¹ can bean aryl group fused to 2 carbon atoms of the cyanoguanidine ringportion; R¹⁴ is hydrogen, alkyl, haloalkyl, aryl, arylalkyl, cycloalkylor (cycloalkyl)alkyl; Y is --O--; Z is NCN; n is an integer of 1 to 3.2. The compounds as recited in claim 1 wherein Y is oxygen;R¹ is##STR119## R² is hydroxyl; R³ and R⁴ are methyl; R⁶ and R⁷ are ethyl; orR⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a 6-membered ring; R⁸ is phenyl; R⁹ is hydrogen; and R¹⁰is hydrogen.
 3. The compounds as recited in claim 1 wherein Y isoxygen;R¹ is ##STR120## R² is hydroxyl; R³ and R⁴ are methyl; R⁶ and R⁷are ethyl; or R⁶ and R⁷ taken together with the nitrogen atom to whichthey are attached form a 6-membered ring; and R¹¹ is hydrogen.
 4. Acompound as recited in claim 1, whichis:(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6- (diethylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans )-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1-piperidinylsulfonyl)-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- (4-morpholinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans,)-N-(4-chlorophenyl)-N"-cyano-N'-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(phenylmethyl)amino!sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans,)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(cyclohexylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimeth-yl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-1- 4-(4-chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-1-2H-benzopyran-6-yl!sulfonyl!-2-piperidinecarboxylicacid, ethyl ester; (3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(phenylamino)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-2-(phenylmethyl)-1-piperidinyl!-sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(2-phenyl-1-piperidinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-4-(phenylmethyl)-1-piperidinyl!-sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-1- 4-(4-chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!-N-ethyl-2-piperidine-carboxamide;(3S-trans)- N- 4-(4-chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-yl!sulfonyl!phenylamino!aceticacid, ethyl ester; (3S-trans)-N-(3-chlorophenyl)-N'- 6-(diethylamino)-sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!urea;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(2-ethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(7S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(3,6,7,8-tetrahydro-7-hydroxy-6,6-dimethyl-2-phenyl-2H-pyrano-2,3-f!-benzisothiazol-8-yl)guanidine, 1,1-dioxide;trans-N-(4-chlorophenyl)-N'-cyano-N"-N-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(3-pyridinylamino)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans;)-N-(4-chlorophenyl)-N'-cyano-N"-N-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(2-phenylethyl)(3-pyridinyl-methyl)amino!sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-N- 6- (2,2-dimethylpropyl)(2phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6- ethyl(2-phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(3-methyl-1-piperidinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(3,3-dimethyl-1-piperidinyl)-sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1-pyrrolidinylsulfonyl)-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(hexahydro-1H-azepin-1-yl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(ethylphenylamino)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-1- 4-(4-chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-1-2H-benzopyran-6-yl!sulfonyl!-3-piperidinecarboxylicacid, ethyl ester; (3S-trans)-4- 4-(4-chlorophenyl)amino!(cyanoimino)-methyl!amino!-3,4-dihydro-3-hydroxy-1-2H-benzopyran-6-yl!sulfonyl!-1-piperazinecarboxylicacid, 1,1-dimethylethyl ester;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(4-methyl-1-piperidinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(2-phenylethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(phenylmethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N- 6-bis(phenylmethyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine;3S- 3a,4b,6(cis)!!-N-(4-chlorophenyl)-N'-cyano-N"- 6-(2,6-dimethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N- 6-bis(2-methylpropyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 6-(cyanomethyl)(3-phenylpropyl)amino!sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;N-(4-chlorophenyl)-N'-cyano-N"- (3S,4R)-6-(3,5-dimethyl-1-piperidinyl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!guanidine;N-(4-chlorophenyl)-N'-cyano-N"-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-3-(phenylmethyl)-1-piperidinyl!-sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N- 6- (3-azabicyclo3.2.2!nonan-3-yl)sulfonyl!-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl!-N'-(4-chlorophenyl)-N"-cyanoguanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- (1,2,3,4-tetrahydro-1-quinolinyl)sufonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"- 3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1,2,3,4-tetrahydro-2-isoquinolinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(1,2,3,4-tetrahydro-2-isoquinolinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine;(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-3,4-dihydro-3-hydroxy-2,2-dimethyl-6-(octahydro-1-quinolinyl)sulfonyl!-2H-1-benzopyran-4-yl!guanidine.
 5. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 6. A method for treating ischemiacomprising administering to a mammalian specie in need thereof atherapeutically effective amount of a composition of claim 5.